Association of Androgen Receptor Exon 1 CAG Repeat Length with Risk of Hepatocellular Carcinoma: a Case-control Study

Overview

Journal Tumour Biol

Publisher Sage Publications

Specialty Oncology

Date 2014 Sep 15

PMID 25217983

Authors

Kainan Li

Chen Zhong

Jun Wang

Baocheng Wang

Jun He

Jingwang Bi

Affiliations

Soon will be listed here.

Abstract

Epidemiologic and biological data suggest a role for androgens and perhaps their receptor in hepatocellular carcinoma (HCC) development. However, few studies evaluated an association between HCC risk and androgen receptor (AR) cytosine, adenine, guanine (CAG) repeat length. To examine whether the relationship between the AR CAG repeats and HCC risk was also evident in Chinese, we conducted this large population-based, case-control study of 2,000 pathologically confirmed HCC patients and 2,000 frequency-matched controls. Two different approaches for AR CAG repeat length (analyses with continuous and categorized polymorphism variables) were conducted in the statistical analyses. For AR CAG longer allele (CAG_L), we found that subjects with longer AR CAG_L repeats had a decreased risk of developing HCC (OR = 0.87 for per CAG_A increase, 95 % CI 0.82-0.96, P = 5.33 × 10(-4)). Compared to those with the shorter (<23) CAG_L repeat length, subjects in the category of longer (≥23) CAG_L repeats had a significant 20 % decreased HCC risk (OR = 0.80, 95 % CI 0.71-0.91, P = 6.16 × 10(-4)). These findings suggest that androgen signaling underlies the development of HCC.

References

Yeh S, Chang C, Shau W, Chen Y, Hsu H, Lee P . Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis. Cancer Res. 2002; 62(15):4346-51. View

FIRMINGER H, Reuber M . Influence of adrenocortical, androgenic, and anabolic hormones on the development of carcinoma and cirrhosis of the liver in A x C rats fed N-2-fluorenyldicetamide. J Natl Cancer Inst. 1961; 27:559-95. View

Liang L, Lu M, Huang J . [Androgen receptor in hepatocellular carcinoma and the surrounding liver tissues in China]. Zhonghua Zhong Liu Za Zhi. 1996; 18(3):214-7. View

Ferro P, Catalano M, Delleva R, Fortunati N, Pfeffer U . The androgen receptor CAG repeat: a modifier of carcinogenesis?. Mol Cell Endocrinol. 2002; 193(1-2):109-20. DOI: 10.1016/s0303-7207(02)00104-1. View

Granata O, Cocciadifero L, Campisi I, Miceli V, Montalto G, Polito L . Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells. J Steroid Biochem Mol Biol. 2009; 113(3-5):290-5. DOI: 10.1016/j.jsbmb.2009.01.013. View

Chang C, Lee S, Yeh S, Chang T . Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogene. 2013; 33(25):3225-34. DOI: 10.1038/onc.2013.274. View

Sleddens H, Oostra B, Brinkmann A, Trapman J . Trinucleotide (GGN) repeat polymorphism in the human androgen receptor (AR) gene. Hum Mol Genet. 1993; 2(4):493. DOI: 10.1093/hmg/2.4.493. View

Zheng J, Li C, Wu X, Yang Y, Hao M, Sheng S . Astrocyte elevated gene-1 is a novel biomarker of epithelial-mesenchymal transition and progression of hepatocellular carcinoma in two China regions. Tumour Biol. 2013; 35(3):2265-9. DOI: 10.1007/s13277-013-1300-3. View

Hsing A, Gao Y, Wu G, Wang X, Deng J, Chen Y . Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Res. 2000; 60(18):5111-6. View

10.

Long X, Zhao D, Wang C, Huang X, Yao J, Ma Y . Genetic polymorphisms in DNA repair genes XRCC4 and XRCC5 and aflatoxin B1-related hepatocellular carcinoma. Epidemiology. 2013; 24(5):671-81. DOI: 10.1097/EDE.0b013e31829d2744. View

11.

Deng Y, Li M, Wang J, Xie L, Li T, He Y . Susceptibility to hepatocellular carcinoma in the Chinese population--associations with interleukin-6 receptor polymorphism. Tumour Biol. 2014; 35(7):6383-8. DOI: 10.1007/s13277-014-1863-7. View

12.

Yu M, Yang Y, Yang S, Chang H, Liaw Y, Lin S . Androgen receptor exon 1 CAG repeat length and risk of hepatocellular carcinoma in women. Hepatology. 2002; 36(1):156-63. DOI: 10.1053/jhep.2002.33897. View

13.

Abdelgadir S, Connolly P, Resko J . Androgen binding in peripheral tissues of fetal rhesus macaques: effects of androgen metabolism in liver. J Steroid Biochem Mol Biol. 1990; 37(4):545-51. DOI: 10.1016/0960-0760(90)90399-6. View

14.

Gao B, Jiang L, Kunos G . Transcriptional regulation of alpha(1b) adrenergic receptors (alpha(1b)AR) by nuclear factor 1 (NF1): a decline in the concentration of NF1 correlates with the downregulation of alpha(1b)AR gene expression in regenerating liver. Mol Cell Biol. 1996; 16(11):5997-6008. PMC: 231602. DOI: 10.1128/MCB.16.11.5997. View

15.

Naveed M, Waljee A, Singal A . Predictive models for hepatocellular carcinoma. Gastroenterology. 2014; 146(5):1420-1. DOI: 10.1053/j.gastro.2014.03.026. View

16.

Parkin D, Bray F, Ferlay J, Pisani P . Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001; 94(2):153-6. DOI: 10.1002/ijc.1440. View

17.

Schildkraut J, Murphy S, Palmieri R, Iversen E, Moorman P, Huang Z . Trinucleotide repeat polymorphisms in the androgen receptor gene and risk of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2007; 16(3):473-80. DOI: 10.1158/1055-9965.EPI-06-0868. View

18.

Wu J, Zhang W, Xu A, Zhang L, Yan T, Li Z . Association of epidermal growth factor and epidermal growth factor receptor polymorphisms with the risk of hepatitis B virus-related hepatocellular carcinoma in the population of North China. Genet Test Mol Biomarkers. 2013; 17(8):595-600. PMC: 3732435. DOI: 10.1089/gtmb.2013.0031. View

19.

Langner A, Nerlich C, Grahlmann D . [Biotransformation of the trapidil (Rocornal) derivative AR 12,463 by the isolated, perfused rat liver and rat hepatocyte suspension cultures]. Pharmazie. 1990; 45(8):636. View

20.

Yeh S, Chiu C, Chen C, Lu S, Hsu H, Chen D . Somatic mutations at the trinucleotide repeats of androgen receptor gene in male hepatocellular carcinoma. Int J Cancer. 2007; 120(8):1610-7. DOI: 10.1002/ijc.22479. View